1.1 Field of the Invention
The present invention provides a method for augmenting proliferation of gastrointestinal epithelial cells. The invention further provides a method for treating or preventing mucositis in patients undergoing cancer treatment, to treat patients with inflammatory bowel disease, and to ameliorate digestion and nutritional absorption of patients with short bowel syndrome.
1.2 Sequence Listing
The sequences of the polynucleotides and polypeptides of the invention are listed in the Sequence Listing and are submitted on a compact disc containing the file labeled “NUVO-21A.ST25.txt”—94.0 KB (96,256 bytes) which was created on an IBM PC, Windows 2000 operating system on Jan. 17, 2006 at 5:14:37 PM. The Sequence Listing entitled “NUVO-21A.ST25.txt” is herein incorporated by reference in its entirety. A computer readable format (“CRF”) and three duplicate copies (“Copy 1/2” and “Copy 2/2”) of the Sequence Listing “NUVO-221A.ST25.txt” are submitted herein. Applicants hereby state that the content of the CRF and Copies 1/1 and 2/2 of the Sequence Listing, submitted in accordance with 37 CFR §1.821 (c) and (e), respectively, are the same.
1.3 Background
Ionizing radiation therapy and cytotoxic chemotherapy produce injuries to the oral and gastrointestinal mucosa, which remain significant problems for patients undergoing antineoplastic treatments. Mucositis is the inflammation of the mucous membranes and is a particularly common problem in this patient population due to the use of chemotherapy and radiation therapy used with curative or palliative intent. The mucosal injuries to the gastrointestinal tract seen with radiation and chemotherapy (to these areas) include the destruction of crypt cells, a decrease in villous height and ulceration and necrosis of the gastrointestinal epithelium (Berthrong M, World J Surg 10:155-170 (1986)), which underlie disorders including gastrointestinal mucositis and enterocolitis. To the patients this can mean abdominal pain, bloody diarrhea, malabsorption and in some cases bacterial translocation (Guzman et al., J Surg Res 46:104-107 (1989)). In addition, chemotherapy and ionizing radiation can affect other mucous membranes including those of the oropharynx and lips, and those of the esophagus. It is well known that combined modality therapy of concurrent radiation and chemotherapy can produce highly symptomatic stomatitis in patients with head and neck cancer, and esophagitis in patients with small cell lung cancer.
Chemotherapy and radiation therapy cause injury to the oral and gastrointestinal mucosa through direct and indirect toxicity. The mechanism for direct mucositis is nonspecific cell killing of rapidly dividing basal epithelial cells that results in epithelial thinning, inflammation, decreased cell renewal, and ultimately ulceration. These painful lesions also produce an increased risk for local and systemic infection. Indirect mucotoxicity is a byproduct of chemotherapy-induced myelosuppression, which permits bacterial and viral infections at the site of direct mucosal injury. The severity of these effects may preclude dose escalation, delay treatment, and warrant dose reductions, thus limiting the effectiveness of cancer therapy.
A well-established prophylaxis or therapy for chemotherapy and radiation therapy-induced (mucosal) gastrointestinal injuries (mucositis) is unavailable, other than a prescription of suboptimal doses of chemotherapy or radiotherapy, a downward dose modification in subsequent treatment courses following toxicity, or the use of specific antidotes such as leucovorin after moderate-dose or high-dose methotrexate (Allegra CJ. Antifolates. In: Chabner and Collins, eds. Cancer Chemotherapy: Principles and Practice. Philadelphia, Pa. JP Lippincott Co; 1990:110-153.)
Injury to the gastrointestinal mucosa is also associated with chronic inflammatory disorders of the gastrointestinal tract, which are collectively referred to as inflammatory bowel disease. While cytokine-based therapies are available for the treatment of inflammatory bowel disease, none can be considered as a permanent cure (Bouma and Strober Nature Rev 3:521-533 (2003)). Often resection of the small intestine is indicated in patients with inflammatory bowel disease such as Crohn's disease. Surgical resection of the small intestine may also be necessary following traumatic injury, vascular accidents, and cancer. Surgical resection that leaves less than 200 cm of viable small bowel places a patient at risk for developing short-bowel syndrome (SBS). SBS is a disorder that is clinically defined by malabsorption, diarrhea, fluid and electrolyte disturbances, and malnutrition. The management of patients with SBS frequently requires long-term, if not life long use of parenteral nutrition DiBaise et al., Am J Gastroenterol 99:1823-1832 (2004)).
Thus, there is a need to find agents that may be used prophylactically or therapeutically to increase the tolerance to anteneoplastic treatments, to advance current therapies for treating inflammatory bowel disease, and to restore the digestive and absorptive processes that are compromised following surgical resection of the intestine.
To this end Applicants have discovered an agent that induces the proliferation of gastrointestinal epithelial cells, and which may be useful for treating conditions in which proliferation of epithelial cells may be desired.